C-14 oxidation of morphine derivatives

ABSTRACT

The present invention relates to process for the preparation of a 14-hydroxynormorphinone derivative of formula IV  
                 
 
comprising reacting the compound of formula III,  
                 
with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant; 
 
wherein R 1  is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R 2  is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen. 
The process is very suitable in the production of noroxymorphone.

The invention relates to a process for the production of14-hydroxynormorphinone derivatives, to a new synthetic route forproducing noroxymorphone, as well as to new intermediates in said route.

Noroxymorphone is a key intermediate for the production of importantmedicinal opioids, such as naltrexone and naloxone. The common startingmaterial for the production of these opioids is thebaine from which theyare readily synthesized. However, thebaine has only a low naturalabundance in poppy heads and opium. As the supply of thebaine is limitedand the demand is increasing, many alternative approaches have been madefor the preparation of 14-hydroxymorphine derivatives. See for exampleEP 0,158,476, U.S. Pat. No. 5,922,876, and the references cited therein.

Further, in an attempt to remove the requirement for (the preparationof) thebaine, Coop et al. (Tetrahedron 55 (1999), 11429-11436; WO00/66588) recently described an oxidative method for the production of14-hydroxycodeinone in a yield of 51% from codeinone, using Co(OAc)₃ asthe metallic oxidant in acetic acid at room temperature. Other oxidativeconditions with metallic oxidants, such as Co(OAc)₃ under otherconditions, FeCl₃, Co(OAc)₂ in combination with several cooxidants,RuO₄, Mn(OAc)₃, Cu(OAc)₂, and others, proved to be not very usefulaccording to Coop.

Surprisingly, and in spite of the findings of Coop, it has now beenfound that in the production of 14-hydroxynormorphinone derivatives offormula IV from compounds of formula III cobalt (II) salts can be usedas efficient oxidants when the reaction is performed in the presence ofa mild base and oxygen or air is used as cooxidant. Therefore, theinvention relates to a process for the preparation of a14-hydroxynormorphinone derivative of formula IV

comprising reacting the compound of formula III,

with a cobalt (II) oxidant in the presence of a mild base and air oroxygen as the cooxidant; wherein R₁ is (1-7C)alkyl optionallysubstituted with one or more chlorines (such as 1,1,1-trichloroethyl),butenyl, vinyl, benzyl, phenyl or naphthyl;and R₂ is benzyl or benzyl substituted with one or more (1-6C)alkoxygroup or benzyl substituted with one or more halogen.

The oxidation process of the present invention is an efficient processwith good yields, which are significantly improved when compared to theprocess described by Coop et al.

The cobalt (II) oxidant according to the present invention may beselected from a range of cobalt (II) salts, such as CoF₂, CoCl₂, CoBr₂,Co(II)sulfate, Co(II)nitrate, Co(II)acetate, Co(II)propionate, and thelike, and mixtures thereof. The preferred oxidant in the process of thisinvention is Co(OAc)₂ and the preferred cooxidant is air. The reactionmixture of this oxidation process is a heterogeneous system; the oxidantdissolves only in minor amounts in the organic solvent that is used. Theamount of cobalt (II) salts used is not very critical, as long as thesystem is heterogeneous, and a skilled person will know to choosesufficient amounts thereof. The cooxidant is introduced into thereaction mixture by bubbling it through the solution, while stirring.

A person skilled in the art is aware what type of base are meant withthe term mild bases, however preferred bases are sodium acetate,potassium acetate, sodium phosphate and potassium phosphate. Mostpreferred is sodium acetate.

Preferably R₁ is (1-7C)alkyl, and most preferred is ethyl. For R₂ benzylis most preferred. The oxidation process according to the presentinvention is performed in an organic solvent well-suited for dissolutionof this type of compounds, preferably (1-4C)alcohols or mixturesthereof. Preferred is ethanol.

The reaction temperature is usually higher than room temperature, andmay be chosen dependent on the boiling point of the solvent used.However, the temperature may not be higher than about 100° C. in orderto keep the oxygen sufficiently in solution.

In the terms (1-7C)alkyl, (1-6C)alkoxy and (1-4C)alcohols the alkylgroup is a branched or unbranched alkyl group having 1 to 7, 1 to 6 or 1to 4 carbon atoms, respectively, such as methyl, ethyl, isopropyl,t-butyl, heptyl and the like.

The compound of formula III may suitably prepared by methods well knownin the art. Preferably, the process for the preparation of a compound offormula III comprises reactively contacting a morphine derivative offormula II

with an oxidizing agent effective for oxidizing allylic hydroxy groupsto form keto groups, where a morphinone compound of the formula III isprepared. Preferably, the oxidizing agent is sodium dichromate.Preferably R₁ is ethyl. For R₂ benzyl is most preferred.

The new process of this invention may conveniently be used in theproduction of noroxymorphone. Therefore, another aspect of thisinvention is a process for the production of noroxymorphone, comprisinga reaction step wherein a morphinone compound of formula III is oxidizedinto the 14-hydroxynormorphinone derivative of formula IV. In particularpreferred is the process further comprising the oxidation of a morphinederivative of formula II into the compound of formula III as describedabove.

Especially preferred is a process for the production of noroxymorphonecomprising the steps:

-   (a) converting morphine having the formula I-    by reaction with a haloformate ester of the formula X—C(═O)OR₁,    wherein R₁ is as previously defined and X is a halogen (F, Cl, Br or    I, preferably Cl),-    followed by a reaction with R₂—X, wherein X (preferably Cl) and R₂    are as previously defined, to form a morphine derivative of formula    II;-   (b) oxidizing the morphine of formula II to form a morphinone    derivative of formula III according to the previously described    process;-   (c) oxidizing the morphinone derivative of formula III to form a    14-hydroxynormorphinone derivative of formula IV according to the    previously described process;-   (d) deprotecting the 3-position and (at the same time) reducing the    double bond at the 7,8-position of the 14-hydroxynormorphinone    derivative of formula IV to form a 3,14-hydroxynormorphinone    derivative of formula V, using methods well known in the art for    such type of reaction, e.g. using hydrogen and palladium-carbon as a    catalyst,-   (e) and hydrolyzing the 3,14-hydroxynormorphinone derivative of    formula V into noroxymorphone of formula VI, using methods well    known in the art for such type of hydrolysis, e.g. using sulfuric    acid,

In the process for the production of noroxymorphone, the novelintermediates of formula II, III and IV form each another aspect of thepresent invention. The intermediates of formula II, III and IV are inparticular preferred wherein R₁ is ethyl. Also preferred areintermediates of formula II, III and IV wherein R₂ is benzyl. Mostpreferred are the intermediates of formula II, III and IV wherein R₁ isethyl and R₂ is benzyl.

The invention is further illustrated by the following example.

EXAMPLE 1

The underlined numbers refer to the numbers of the structures of SchemeI. (Bn=benzyl).

(5α,6α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-hydroxymorphinan-17-carboxylicacid ethylester (2)

Morphine (1, 8 g) was dissolved in 80 ml of toluene and the solution wasdried by azeotropic distillation of water. Sodium carbonate (15 g) andsodium hydrogen carbonate (6 g) were added and the solution was againdried by azeotropic distillation. Ethyl chloroformate (30 g) was slowlyand in portions added over a period of approximately 4 h at 78° C.Completion of the reaction was checked with TLC. The excess of reagentand the salts were dissolved by addition of water. The layers wereseparated and the toluene layer was washed with water. The toluenesolution was evaporated to dryness and the residue was dissolved in 70ml of ethanol. The 3-carboxylic acid ethyl ester group was saponified by6 g potassium hydroxide (dissolved in 18 ml of ethanol) and 5 gpotassium carbonate at 55° C. The pH was checked (in a 1:1 dilution inwater) and was >11. To this basic solution 5 g benzylchloride was addedand the reaction was performed for 4 h at 75° C. The product wasprecipitated by the addition of water (70 ml), filtered, washed withwater and dried. The yield of product (2) was 10 g. ¹H NMR (600 M,CDCl₃) δ 1.29 (m, 3H), 1.92 (m, 2H), 2.52 (s, 1H), 2.72 (m, 2H), 2.85(m, 1H), 3.01 (m, 1H), 4.01 (m, 1H), 4.17 (m, 3H), 4.87 (d, 1H), 4.89(d, 1H), 5.09 (d, 1H), 5.18 (d, 1H), 5.29 (t, 1H), 5.72 (t, 1H), 6.53(d, 1H), 6.75 (d, 1H), 7.37 (m, 5H).

(5α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-oxomorphinan-17-carboxylicacid ethylester (3)

A solution of Jones reagent was prepared by dissolving 7,5 g sodiumdichromate.2H₂O in 22 ml water and 6 ml sulfuric acid. Compound (2) (7,5g) was dissolved in 60 ml trichloro ethylene and 28 ml water was added.The pH was adjusted to 5 with sulfuric acid. The mixture was heatedunder reflux and the Jones reagens was slowly added over a period of 1h. The oxidation was continued for another 1,5 h under reflux. Theexcess of oxidant was destroyed with 6 ml 2-propanol. The layers wereseparated and the organic layer was washed with 10% sodium hydrogencarbonate solution and water and dried with sodium sulfate. The solutionwas evaporated to dryness and the residue was dissolved in ethanol.Yield: ˜9 g product (3). ¹H NMR (200 MHz, CDCl₃) δ 1.28 (m, 3H), 1.92(m, 2H), 2.8 (m, 2H), 2.9 (m, 1H), 3.05 (m, 1H), 4.02 (m, 1H), 4.19 (m,2H), 4.72 (s, 1H), 5.03 (m, 1H), 5.18 (s, 2H), 6.12 (dd, 1H), 6.57 (d,1H), 6.64 (in, 1H), 6.74 (d, 1H), 7.34 (m, 5H).

(5α-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-14-hydroxy-6-oxomorphinan-17-carboxylicacid ethylester (4)

The solution of product (3) in ethanol (9 g in 135 ml) was heated to 60°C., 2,6 g cobalt (II) acetate and 0,5 g sodium acetate were added andair was bubbled through the solution under vigorous stirring. Thereaction was followed with TLC. After completion of the reaction thesolution was treated with charcoal (0,3 g) and filtered. The solutionwas distilled to volume and this concentrated solution (6,3 g (4) in 53ml of ethanol) was transferred to the next step. ¹H NMR of 4 (360 MHz,CH₃OH-d4) δ 1.28 (m, 3H), 1.55 (m, 1H), 2.52 (m, 1H), 2.74 (m, 1H), 2.92(m, 2H), 4.05 (m, 1H), 4.15 (m, 2H), 4.64 (m, 1H), 4.72 (s, 1H), 4.85(m, 1H), 5.1 (s, 2H), 6.05 (d, 1H), 6.6 (d, 1H), 6.76 (d, 1H), 6.91 (m,1H), 7.3 (m, 5H).

(5α)-4,5-epoxy-3,14-dihydroxy-6-oxomorphinan-17-carboxylic acidethylester (5)

To the solution of the previous step 6 ml of acetic acid was added. Theproduct (4) was reduced with hydrogen and palladium-carbon (5%) as acatalyst (0,9 g) at 20° C. and normal pressure. After filtration andevaporation of ethanol 5,4 g of crude product (5) was obtained. Theproduct was recrystallized from 2 parts (w/v) of ethyl acetate to obtain4,7 g product (5).

(5α)-4,5-epoxy-3,14-dihydroxymorphinan-6-one (noroxymorphone) (6)

Product (5) (4,7 g) was dissolved in 28 ml of water and 5,6 ml ofsulfuric acid and refluxed for approx. 24 h. The product wasprecipitated at pH=9 by dilution with water and 4,6 g of crude product(6) was obtained after filtration and drying. The product was purifiedby dissolution in ethanol, precipitation from this solvent at pH=2,dissolution in water, charcoal treatment and precipitation at pH=9. ¹HNMR (400 M z, DMSO-d6) δ 1.17 (m, 1H), 1.41 (m, 1H), 1.72 (m, 1H), 2.07(m, 1H), 2.29 (m, 1H), 2.36 (m, 1H), 2.62 (in 1H), 3.9 (m, 4H), 4.68 (s,1H), 6.52 (d, 1H), 6.56 (d, 1H).

1. A process for the preparation of a 14-hydroxynormorphinone derivativeof formula IV

comprising reacting the compound of formula III,

with a cobalt (II) oxidant in the presence of a mild base and air oroxygen as the cooxidant; wherein R₁ is (1C-7C)alkyl optionallysubstituted with one or more chlorines, butenyl, vinyl, benzyl, phenylor naphthyl; and R₂ is benzyl or benzyl substituted with one or more(1C-6C)alkoxy group or benzyl substituted with one or more halogen. 2.The process of claim 1, wherein the oxidant is Co(OAc)₂.
 3. The processof claim 1, wherein the cooxidant is oxygen.
 4. The process of claim 1,wherein the mild base is sodium acetate, potassium acetate, sodiumphosphate or potassium phosphate.
 5. The process of claim 4, wherein themild base is sodium acetate.
 6. The process of claim 1, wherein R₁ is(1-7C)alkyl.
 7. The process of claim 6, wherein R₁ is ethyl.
 8. Theprocess of claim 1, wherein R₂ is benzyl.
 9. A 14-hydroxynormorphinonederivative of the formula IV

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 10. The 14-hydroxynormorphinonederivative of claim 9, wherein R₁ is ethyl.
 11. The14-hydroxynormorphinone derivative of claim 9, wherein R₂ is benzyl. 12.A morphinone derivative of the formula III

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 13. The morphinone derivative ofclaim 12, wherein R₁ is ethyl.
 14. The morphinone derivative of claim12, wherein R₂ is benzyl.
 15. A process for the preparation of acompound of formula III, comprising:

reactively contacting a morphine derivative of formula II with anoxidizing agent effective for oxidizing allylic hydroxy groups to formketo groups, where the compound of formula III according to claim 12 isprepared.
 16. The process of claim 15, wherein the oxidizing agent issodium dichromate.
 17. The process of claim 15, wherein R, is ethyl andR₂ is benzyl.
 18. A morphine derivative of formula II

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 19. The morphine derivative ofclaim 18, wherein R₁ is ethyl.
 20. The morphine derivative of claim 17,wherein R₂ is benzyl.
 21. A process for the production ofnoroxymorphone, comprising: a reaction step wherein a morphinonederivative of formula III

is oxidized into a 14-hydroxynormorphinone derivative of formula IV

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 22. A process for the productionof a compound of formula III, comprising: oxidizing a compound offormula II

to form a morphinone derivative of formula III wherein R₁ is(1C-7C)alkyl optionally substituted with one or more chlorines, butenyl,vinyl, benzyl, phenyl or naphthyl; and R₂ is benzyl or benzylsubstituted with one or more (1C-6C)alkoxy group or benzyl substitutedwith one or more halogen.
 23. A process for the production ofnoroxymorphone, wherein morphine is converted into noroxymorphone,comprising: (a) converting morphine having the formula I

 by reaction with a haloformate ester of the formula X—C(═O)OR₁, whereinR₁ is (1C-7C)alkyl optionally substituted with one or more chlorines,butenyl, vinyl, benzyl, phenyl or naphthyl and X is a halogen, followedby a reaction with R₂—X, wherein X is as previously defined and R₂ isbenzyl or benzyl substituted with one or more (1C-6C)alkoxy group orbenzyl substituted with one or more halogen, to form a morphinederivative of formula II

(b) oxidizing the morphine of formula II to form a morphinone derivativeof formula III

wherein the process is reactively contacting a morphine derivative offormula II with an oxidizing agent effective for oxidizing allylichydroxy groups to form keto groups; (c) oxidizing the morphinonederivative of formula III to form a 14-hydroxynormorphinone derivativeof formula IV according to process according to claim 1; (d)deprotecting the 3-position and reducing the double bond at the7,8-position of the 14-hydroxynormorphinone derivative of formula IV toform a 3,14-hydroxynormorphinone derivative of formula V,

(e) and hydrolyzing the 3,14-hydroxynormorphinone derivative of formulaV into noroxymorphone of formula VI,